Cholecystokinin inhibits peripheral opioid analgesia in inflamed tissue.
There is abundant evidence that opioid receptors are present on peripheral terminals of primary afferent neurons. Experimental and clinical studies have shown that activation of these peripheral opioid receptors produces potent analgesia. In addition to peripheral opioid receptors, cholecystokinin receptors are present in sensory neurons. We examined the hypothesis that cholecystokinin receptors may be present on the same primary afferent neuron and that either exogenous or endogenous cholecystokinin may modulate peripheral antinociceptive effects of mu-opioid receptor agonists. Administration of cholecystokinin into inflamed paws, of the rat, but not intravenously attenuated peripheral antinociceptive effects induced by two mu-opioid receptor agonists, [D-Ala2,N-methyl-Phe4,Gly-ol5]-enkephalin and fentanyl. Only the desulphated form of cholecystokinin produced significant and dose-dependent attenuation. Cholecystokinin alone did not alter nociceptive baseline values in inflamed or non-inflamed paws. The anti-opioid effect of cholecystokinin was dose-dependently antagonized by the cholecystokininB receptor-selective antagonist L-365260, but not by the cholecystokininA receptor-selective antagonist L-364718. Local pretreatment with the protein kinase C specific inhibitor calphostin C abolished cholecystokinin's effect. Peripheral antinociceptive effects of [D-Ala2,N-methyl-Phe4,Gly-ol5]-enkephalin and fentanyl were not altered by intraplantar L-365260 alone. These results indicate that activation of peripheral cholecystokininB but not cholecystokininA receptors attenuates the local antinociceptive effects of mu-opioid receptor agonists in inflamed tissue. This anti-opioid effect may be mediated by protein kinase C in sensory nerve terminals. Endogenous cholecystokinin does not seem to influence the efficacy of peripheral opioids under both normal and inflammatory conditions.
Schäfer
M
M
Behavioral Pharmacology and Genetics Section, Division of Intramural Research, National Institute on Drug Abuse, Baltimore, MD 21224, USA.
Zhou
L
L
Stein
C
C
D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D002766:Cholecystokinin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005283:Fentanyl / Q000494:pharmacology; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000150:complications* / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors
D000701:Analgesics, Opioid; D004745:Enkephalins; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D011949:Receptors, Cholecystokinin; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D002766:Cholecystokinin; D011493:Protein Kinase C; C058819:calphostin C; D005283:Fentanyl